The present invention relates to a nitrogen-containing heterocyclic compound derivative useful as a phosphodiesterase-4 inhibitor, its salt or hydrates thereof, and a medicament comprising the same. More specifically, it relates to a prophylactic and therapeutic agent comprising a nitrogen-containing heterocyclic compound, its salt or hydrates thereof for inflammatory diseases, asthma, autoimmune disease such as allograft rejection, graft versus host disease, chronic joint rheumatism and multiple sclerosis, sepsis, psoriasis, osteoporosis or diabetes.
In a group of a series of decomposition enzymes called phosphodiesterase (referred to hereinafter as xe2x80x9cPDExe2x80x9d), the presence of 7 families of PDE1 to PDE7 is confirmed. One family PDE4 is an enzyme specific to a secondary messenger, cyclic adenosine-3xe2x80x2,5xe2x80x2-monophosphate (cyclic AMP), and is known to regulate the concentration of cyclic AMP by decomposition. Cyclic AMP is increased in vivo upon stimulation with hormone, to exhibit a wide variety of physiological actions such as formation of specific enzymes or regulation of metabolic functions, and in e.g. human leukocytes, cyclic AMP has an important role in activation of cells and regulation of immune response. Under this background, the physiological significance of PDE4 has been regarded as important in recent years, and it is expected that a PDE4 inhibitor can work effectively as a prophylactic and therapeutic agent against various diseases in which cyclic AMP is involved. For example, since PDE4 is present widely in mast cells eosinophils monocytes macrophages T-lymphocytes, epithelial cells, and respiratory smooth muscles, there have been proposed the possibility of the PDE4 inhibitor as an anti-asthma agent (Clin. Exp. Allergy, 22, 337-44, 1992) and the possibility of the PDE4 inhibitor as an agent for treating arthritis, cachexia, multiple sclerosis and sepsis on the basis of a report on the inhibition of tumor-necrosis-factor xcex1 (TNFxcex1) by the PDE4 inhibitor (Int. J. Immunopharmacol., 15, 409-13, 1993; Int. J. Immunopharmacol., 16, 805-16, 1994). With these findings as the background, a large number of reports on those compounds inhibiting PDE4 have been made. For example, JP-A 5-229987 and JP-A 9-59255 disclose an invention relating to naphthalene compounds as PDE4 inhibitors. On the other hand, JP-B 40-20866 and JP-B 6-192099 disclose an invention relating to quinazoline compounds as inhibitors of production of TNFxcex1.
Heretofore, theophylline is famous as a PDE4 inhibitor, but is poor in specificity for PDE4 and inhibits the PDE family unspecifically, thus bringing about side effects in cardiac blood vessels or in the central system. Further, other PDE4 inhibitors also cause the problems of nausea, emesis, headache etc., and therefore, none of effective PDE4 inhibitors have been created.
Under these circumstances, the present inventors made extensive study for the purpose of providing a PDE4 inhibitor effective for the inflammatory diseases and immune diseases. As a result, they found that a nitrogen-containing heterocyclic compound having a novel structure, its salt or hydrates thereof, exhibit superior activity as a PDE4 inhibitor, and also that it is useful as an inhibitor of production of TNFxcex1. Further, the present inventors found that the PDE4 inhibitor of the present invention has the action of lowering blood sugar and is useful as a prophylactic and therapeutic agent for diabetes. Thus, they have accomplished the present invention.
That is, the present invention relates to a nitrogen-containing heterocyclic compound represented by the following formula, its salt or hydrates thereof, and a medicament comprising the same. 
Wherein the ring A is an aromatic hydrocarbon ring which may have a heteroatom,
the ring B represents:
1) a saturated hydrocarbon ring which may have a substituent group,
2) an unsaturated hydrocarbon ring which may have a substituent group,
3) a saturated heterocyclic ring which may have a substituent group or
4) an unsaturated heterocyclic ring which may have a substituent group,
R1 represents:
1) hydrogen atom,
2) a halogen atom,
3) a C1-6 alkyl group which may be substituted with a halogen atom,
4) a C1-6 alkoxy group which may be substituted with a halogen atom or
5) an amino group which may be substituted with a C1-6 alkyl group or an acyl group,
R2 and R3 are the same as or different from and represent:
1) hydrogen atom,
2) a C1-6 alkyl group which may have a substituent group,
3) a C3-7 cycloalkyl group which may have a substituent group,
4) a C2-6 alkenyl group which may have a substituent group or
5) an acyl group,
R4, R5, R6 and R7 are the same as or different from and represent:
1) hydrogen atom,
2) a halogen atom,
3) a C1-6 alkyl group which may be substituted with a halogen atom,
4) a C3-7 cycloalkyl group which may have a substituent group,
5) an aryl group which may have a substituent group,
6) a C1-6 alkoxy group which may have a substituent group,
7) a C3-7 cycloalkoxy group which may have a substituent group,
8) an aryl alkoxy group which may have a substituent group, or
9) a C1-6 alkylthio group which may have a substituent group,
10) a hydroxyl group,
11) an amino group which may be substituted with a C1-6 alkyl group or an acyl group,
12) a nitro group,
13) a cyano group,
14) a carboxyl group or
15) a C1-6 alkoxy carbonyl group, or
16) neighboring R3, R4, R5 and R6 may be combined to form a ring which may be substituted with a C1-6 alkyl group, and the ring being a ring which may form a heterocyclic ring containing one or more atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
L represents:
1) a single bond,
2) a C1-6 alkylene group which may have a substituent group,
3) a C2-6 alkenylene group which may have a substituent group,
4) a C2-6 alkynylene group which may have a substituent group, or
5) a group represented by the formula xe2x80x94Exe2x80x94Gxe2x80x94 (wherein E represents:
a) an oxygen atom,
b) a sulfur atom,
c) formula xe2x80x94COxe2x80x94,
d) xe2x80x94SOxe2x80x94,
e) xe2x80x94SO2xe2x80x94,
f) xe2x80x94N(R2)xe2x80x94 (wherein R8 represents hydrogen atom, a C1-6 alkyl group or an acyl group),
g) xe2x80x94N(R9)xe2x80x94COxe2x80x94 (wherein R9 represents hydrogen atom or a C1-6 alkyl group) or
h) xe2x80x94(CH2)mxe2x80x94 which may have a substituent group (wherein m is an integer of 0 to 6), and G. represents:
a) a sulfonyl group,
b) formula xe2x80x94N(R10)xe2x80x94 (wherein R10 represents hydrogen atom, a C1-6 alkyl group or an acyl group), or
c) xe2x80x94(CH2)nxe2x80x94 (wherein n is an integer of 0 to 6)), and X and Y are the same as or different from each other and each represents:
1) a nitrogen atom,
2) xe2x95x90CHxe2x80x94 or
3) a carbon atom which may be substituted with a C1-6 alkyl group which may have a substituent group, provided that X and Y are not simultaneously carbon atoms which may be substituted with a C1-3 alkyl group.
Preferably, X and/or Y is a nitrogen atom.
Further, the present invention provides a phosphodiesterase-4 inhibitor comprising the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof. In addition, it provides an inhibitor of production of TNFxcex1, comprising the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof. Furthermore, it provides a pharmaceutical composition comprising a pharmacologically effective amount of the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof and a pharmaceutically acceptable carrier. Also, it provides a method of preventing or treating diseases against which an inhibitory action on phosphodiesterase-4 is effective for therapy, which comprises administering a pharmacologically effective amount of the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof to a patient for whom an inhibitory action on phosphodiesterase-4 is effective for therapy. Further, it provides use of the above-mentioned nitrogen-containing heterocyclic compound, its salt or hydrates thereof in production of a phosphodiesterase-4 inhibitor.
The present invention also encompasses nitrogen-containing heterocyclic compound shown in the following mode, its salt or hydrates thereof.
That is, in the formula,
the ring A is a monocyclic or bicyclic aryl group which may have a substituent group and a heteroatom,
the ring B represents:
1) a C3-7 cycloalkyl group which may have a substituent group and a heteroatom, or
2) a monocyclic or bicyclic unsaturated cycloalkyl group which may have a substituent group and a heteroatom,
R1 represents:
1) a hydrogen atom,
2) a halogen atom,
3) a straight-chain or branched C1-6 alkyl group which may be substituted with a halogen atom,
4) a C1-6 alkoxy group which may be substituted with a halogen atom, or
5) an amino group which may be substituted with a C1-6 alkyl or acyl group,
R2 and R3 are the same or different and represent:
1) hydrogen atom,
2) a straight or branched C1-6 alkyl group which may be substituted with a halogen atom,
3) a C3-7 cycloalkyl group,
4) a C2-4 alkenyl group, or
5) an acyl group,
R4, R5, R6 and R7 are the same or different and represent:
1) hydrogen atom,
2) a halogen atom,
3) a straight or branched C1-6 alkyl group which may be substituted with a halogen atom,
4) a C3-7 cycloalkyl group,
5) an aryl group which may have a substituent group,
6) a C1-6 alkoxy group which may be substituted with a halogen atom,
7) a C3-7 cycloalkoxy group,
8) an aryl alkoxy group which may have a substituent group,
9) a C1-6 alkylthio group,
10) a hydroxy group,
11) an amino group which may be substituted with a C1-6 alkyl group or an acyl group,
12) a nitro group,
13) a cyano group,
14) a carboxyl group or
15) a C1-6 alkoxycarbonyl group, or
16) neighboring R3, R4, R5 and R6 may be combined to form an alkylene dioxy ring which may be substituted with a C1-3 alkyl group,
L represents:
1) a C1-6alkylene group which may have a substituent group,
2) a C2-6, alkenylene group which may have a substituent group,
3) a C2-6 alkynylene group which may have a substituent group, or
4) formula xe2x80x94Exe2x80x94Gxe2x80x94, (wherein E represents:
a) an oxygen atom,
b) a sulfur atom which may be oxidized,
c) an alkylene group represented by the formula xe2x80x94(CH2)mxe2x80x94which may have a substituent group, wherein m is 0 or an integer of 1 to 6,
d) a group shown in the formula xe2x80x94COxe2x80x94,
e) a group represented by the formula xe2x80x94N(R8)xe2x80x94 (wherein
R8 represents hydrogen atom, a C1-6 alkyl group or an acyl group) or
f) a group represented by the formula xe2x80x94N(R9)xe2x80x94 (wherein
R9 represents a hydrogen atom or a C1-6 alkyl group, and G represents:
a) a sulfonyl group,
b) formula xe2x80x94N(R10)xe2x80x94 (wherein R10 represents hydrogen atom, a C1-6 alkyl group or an acyl group), or
c) formula xe2x80x94N(CH2)xe2x80x94 (wherein n is 0 or an integer of 1 to 6), provided that when both E and G are alkylene groups, L is a C1,6 alkylene group), and
X and Y are the same as or different from each other and each represent:
1) a nitrogen atom, or
2) a carbon atom which may be substituted with a C1-6 alkyl group, provided that X and Y are not simultaneously carbon atoms which may be substituted with a C1-3 alkyl group.
The present invention is as described above, and preferably it is a nitrogen-containing heterocyclic compound of the formula (I), wherein the ring A is a benzene or pyridine ring which may have a substituent group; and the ring B is an unsaturated hydrocarbon ring which may have a substituent group or an unsaturated heterocyclic ring which may have a substituent group, its salt or hydrates thereof, and is a medicament comprising the same.
More preferably, it is a nitrogen-containing heterocyclic compound of the formula (I), wherein the ring A is a benzene or pyridine ring which may have a substituent group; the ring B is an aromatic hydrocarbon ring which may have a substituent group or an aromatic heterocyclic ring which may have a substituent group; Lisa single bond, C1-6 alkylene group, C2-6 alkenylene group, C2-6 alkynylene group, the formula xe2x80x94N(R8)xe2x80x94COxe2x80x94(CH2)1xe2x80x94 (wherein R8 has the same meanings as defined above and 1 is an integer of 0 to 6), xe2x80x94N(R8)xe2x80x94SO2xe2x80x94 (wherein R8 has the same meanings as defined above), xe2x80x94N (R8)xe2x80x94 (CH2)1xe2x80x94 (wherein R8and 1 have the same meanings as defined above) or xe2x80x94COxe2x80x94N(R10)xe2x80x94 (wherein R10 has the same meanings as defined above); and both X and Y are nitrogen atoms, its salt or hydrates thereof, and is a medicament comprising the same.
Further preferably, it is a nitrogen-containing heterocyclic compound of the formula (I), wherein the ring A is a benzene or pyridine ring; the ring B is a C3-7 hydrocarbon ring which may have a substituent group, a benzene ring which may have a substituent group, a naphthalene ring which may have a substituent group, a pyridine ring which may have a substituent group, a pyrrole ring which may have a substituent group, a quinoline ring which may have a substituent group, an imidazopyridine ring which may have a substituent group, an isoindole ring, a phthalimide ring or a benzene ring which may be substituted with an alkylene dioxy group; L is a single bond, xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, the formula xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94NHxe2x80x94SO2xe2x80x94; both X and Y are nitrogen atoms; R2 and R3 are the same as or different from and represent hydrogen atom or a C1-6 alkyl group which may be substituted with a halogen atom; both R4 and R7 are hydrogen atoms, R5 and R6 are the same as or different from and represent a C1-6 alkoxy group which may be substituted with a halogen atom, a C3-7 cycloalkoxy group which may have a substituent group, an aryl group which may have a substituent group or an aryl alkoxy group, its salt or hydrates thereof, and is a medicament comprising the same.
In the specification, the structural formulae of these compounds may, for convenience"" sake, indicate a certain isomer, but the present invention encompasses every possible isomer such as geometric isomer, optical isomer, stereoisomer and tautomer based on asymmetric carbon, which can occur in the structures of these compounds, and mixtures of such isomers, and is not limited to the formulae shown for convenience, sake.
Hereinafter, the words and phrases used in the specification are described more in detail.
In the formula (I), the phrase xe2x80x9cwhich may have a substituent groupxe2x80x9d in the definition of the ring A means that the ring A may be substituted with a substituent group such as hydroxyl group; thiol group; nitro group; morpholino group; thiomorpholino group; halogen atom such as fluorine, chlorine, bromine and iodine; nitrile group; azide group; formyl group; alkyl group such as methyl group, ethyl group, propyl group, isopropyl group and butyl group; alkenyl group such as vinyl group, allyl group and propenyl group; alkynyl group such as ethynyl group, butynyl group and propargyl group; alkoxy group such as methoxy group, ethoxy group, propoxy group and buthoxy group corresponding to a lower alkyl group; halogenoalkyl group such as fluoromethyl group, difluoromethyl group, trifluoromethyl group and halogenoethyl group; hydroxyalkyl group such as hydroxymethyl group, hydroxyethyl group and hydroxypropyl group; guanidino group; formimidoyl group; acetoimidoyl group; carbamoyl group; thiocarbamoyl group; carbamoyl alkyl group such as carbamoyl methyl group and carbamoyl ethyl group; alkyl carbamoyl group such as methyl carbamoyl group and dimethyl carbamoyl group; carbamide group; alkanoyl group such as acetyl group; amino group; alkyl amino group such as methyl amino group, ethyl amino group and isopropyl amino group; dialkyl amino group such as dimethyl amino group, methyl ethyl amino group and diethyl amino group; amino alkyl group such as amino methyl group, amino ethyl group and amino propyl group; carboxy group; alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group; alkoxycarbonyl alkyl group such as methoxycarbonyl methyl group, ethoxycarbonyl methyl group, propoxycarbonyl methyl group, methoxycarbonyl ethyl group, ethoxycarbonyl ethyl group and propoxycarbonyl ethyl group; alkyloxyalkyl group such as methyloxymethyl group, methyloxyethyl group, ethyloxymethyl group and ethyloxyethyl group; alkylthioalkyl group such as methylthiomethyl group, methylthioethyl group, ethylthiomethyl group and ethylthioethyl group; aminoalkyl aminoalkyl group such as aminomethyl aminomethyl group and aminoethyl aminoethyl group; alkyl carbonyloxy group such as methyl carbonyloxy group, ethyl carbonyloxy group and isopropyl carbonyloxy group; cycloalkoxy group such as cyclopropoxy group, cyclobuthoxy group, cyclopenthoxy group and cyclohexanoxy group; arylalkoxy group such as phenoxy group, benzyloxy group and phenethyloxy group; arylalkoxy alkoxy alkyl group such as benzyloxy methyl oxymethyl group and benzyloxy ethyloxy ethyl group; hydroxyalkoxyalkyl group such as hydroxyethyloxymethyl group and hydroxyethyloxyethyl group; arylalkoxyalkyl group such as benzyloxymethyl group, benzyloxyethyl group and benzyloxypropyl group; quaternary ammonio group such as trimethyl ammonio group, methyl ethyl methyl ammonio group and triethyl ammonio group; cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group; cycloalkenyl group such as cyclopropenyl group, cyclobutenyl group, cyclopentenyl group and cylohexenyl group; aryl group such as phenyl group, pyridinyl group, thienyl group, furyl group and pyrrolyl group; alkylthio group such as methylthio group, ethylthio group, propylthio group and butylthio group; arylthio group such as phenylthio group, pyridinylthio group, thienylthio group, furylthio group and pyrrolylthio group; aryl lower alkyl group such as benzyl group, trityl group and dimethoxy trityl group; substituted sulfonyl group such as sulfonyl group, mesyl group and p-toluene sulfonyl group; aryloyl group such as benzoyl group; halogenoaryl group such as fluorophenyl group and bromophenyl group; and oxyalkoxy group such as methylene dioxy group.
Hereinafter, the phrase xe2x80x9cmay have a substituent groupxe2x80x9d in the specification has the same meaning as defined above.
The heteroatom in the phrase xe2x80x9cmay have a heteroatomxe2x80x9d means an oxygen atom, sulfur atom, nitrogen atom, phosphorus, antimony, bismuth, silicon, germanium, tin and lead, preferably an oxygen atom, sulfur atom and nitrogen atom, more preferably a nitrogen atom.
Hereinafter, the heteroatom in the phrase xe2x80x9cmay have a heteroatomxe2x80x9d in the specification has the same meaning as defined above.
The aromatic hydrocarbon ring means a benzene ring, pentalene ring, indene ring, naphthalene ring, azulene ring, heptalene ring and benzocycloctene ring. The aryl ring means groups based on the above-mentioned aromatic hydrocarbon rings.
The phrase xe2x80x9caromatic hydrocarbon ring which may have a heteroatomxe2x80x9d means an aromatic heterocyclic ring, that is, an aromatic hydrocarbon ring wherein any of 1 to 4 carbon atoms in an aromatic hydrocarbon ring having the same meaning as defined above may be a heteroatom. Examples of such aromatic heterocyclic rings include a pyridine ring, pyrrole ring, imidazole ring, pyrazole ring, pyrazine ring, pyrimidine ring, pyridazine ring, thiophene ring, furan ring, pyran ring, isothiazole ring, isoxazole ring, furazane ring, indolyzine ring, indole ring, isoindole ring, indazole ring, purine ring, quinolidine ring, isoquinoline ring, phthalazine ring, naphthylidine ring, quinoxaline ring, quinazoline ring, cinoline ring, pteridine ring, benzothiophene ring, isobenzofuran ring, benzoxazole ring, benzthiazole ring, benzthiadiazole ring, benzimidazole ring, imidazopyridine ring, pyrrolopyridine ring, pyrrolopyrimidine ring and pyridopyrimidine ring, among which a pyridine ring, pyrimidine ring, imidazole ring and quinoline ring are preferable.
In the specification, the heteroaryl group means groups based on the above-mentioned aromatic heterocyclic rings.
In the formula (I), the phrase xe2x80x9cC3-7 saturated hydrocarbon ring which may have a substituent groupxe2x80x9d in the ring B means e.g. 3- to 7-memberred rings such as cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane, and these hydrocarbon rings may have substituent groups having the same meanings as defined above.
In the specification, the C3-7 cycloalkyl group means groups based on the above-mentioned C3-7 saturated hydrocarbon rings.
The saturated heterocyclic ring means rings wherein any of 1 to 4 carbon atoms in the above-mentioned C3-7 saturated hydrocarbon rings is a heteroatom, and examples of such rings include aziridine, pyrrolidine, piperidine, imidazolidine, pyrazolidine, piperazine, morpholine, oxysilane and oxathiolane. These saturated heterocyclic rings may have substituent groups having the same meanings as defined above.
The phrase xe2x80x9cunsaturated hydrocarbon ring which may have a substituent groupxe2x80x9d means a C3-7 saturated hydrocarbon ring having the same meanings as defined above except that the ring has a carbon-carbon double bond, and examples of such rings include monocyclic or bicyclic unsaturated hydrocarbon rings such as cyclopropene, cyclobutene, cyclopentene, cyclohexene and cycloheptene or aromatic hydrocarbon rings having the same meanings as defined above.
The unsaturated heterocyclic ring means an unsaturated hydrocarbon ring having the same meanings as defined above except that any of 1 to 4 carbon atoms therein is a heteroatom, and example of such rings include the same aromatic heterocyclic rings as defined above and unsaturated condensed rings such as phthalimide and succinimide. These unsaturated heterocyclic rings may have substituent groups having the same meanings as defined above.
In the phase xe2x80x9cmay be substituted with a halogen atomxe2x80x9d in R1 in the formula (I), the halogen atom means fluorine, chlorine, bromine, iodine.
Hereinafter, the halogen atom in the specification has the same meanings as defined above.
Examples of the C1-6 alkyl group include straight or branched C1-6 alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, sec-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n-pentyl group, i-pentyl group, sec-pentyl group, t-pentyl group, n-hexyl group, i-hexylgroup, 1,2-dimethyl propyl group, 2-ethyl propyl group, 1-methyl-2-ethyl propyl group, 1-ethyl-2-methyl propyl group, 1,1,2-trimethyl propyl group, 1,2,2-trimethyl propyl group, 1,1-dimethyl butyl group, 2,2-dimethyl butyl group, 2-ethyl butyl group, 1,3-dimethyl butyl group, 2-methyl pentyl group and 3-methyl pentyl group, preferably methyl group, ethyl group, n-propyl group, i-propyl group, sec-propyl group, t-propyl group, n-butyl group, i-butyl group, sec-butyl group, n-pentyl group, i-pentyl group, sec-pentyl group, t-pentyl group, n-hexyl group, i-hexyl group, 1,2-dimethyl propyl group, 2-ethyl propyl group, 1,1-dimethyl butyl group, 2,2-dimethyl butyl group, 2-ethyl butyl group, 1,3-dimethyl butyl group, 2-methyl pentyl group and 3-methyl pentyl group, more preferably methyl group, ethyl group, n-propyl group, i-propyl group, sec-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, 1,2-dimethyl propyl group, 2-ethyl propyl group, 1,1-dimethyl butyl group, 2,2-dimethyl butyl group, 2-ethyl butyl group and 1,3-dimethyl butyl group, further preferably methyl group, ethyl group, n-propyl group, i-propyl group, t-propyl group, 1,2-dimethyl propyl group and 2-ethyl propyl group, and most preferably methyl group, ethyl group, n-propyl group, i-propyl group and sec-propyl group.
Hereinafter, the C1-6 alkyl group in the specification has the same meanings as defined in above.
The xe2x80x9cC1-6 alkyl group which may be substituted with a halogen atomxe2x80x9d means the C1-6 alkyl group defined above provided that any of carbon atoms therein may be substituted with the halogen atom defined above, and examples of such groups include a trifluoromethyl group, 2-chloroethyl group, 1,2-dichloroethyl group, 2-bromoethyl group, 3-bromopropyl group, 3,3,3-trifluoropropyl group, 4-chlorobutyl group, 1,1-dimethyl-3-chloroethyl group and 2,2-dimethyl-4-bromobutyl group.
In the specification, the xe2x80x9cC1-6 alkyl group which may be substituted with a halogen atomxe2x80x9d has the same meanings as defined above.
The C1-6 alkoxy group includes alkoxy groups that correspond to the C1-6 alkyl groups defined above, and specifically, this group includes a methoxy group, ethoxy group, n-propoxy group, i-propoxy group, sec-propoxy group, n-buthoxy group, i-buthoxy group, sec-buthoxy group, t-buthoxy group, n-pentyloxy group, i-pentyloxy group, sec-pentyloxy group, t-pentyloxy group, n-hexyloxy group, i-hexyloxy group, 1,2-dimethylpropoxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentyloxy group and 3-methylpentyloxy group. The phrase xe2x80x9cC1-6 alkoxy group which may be substituted with a halogen atomxe2x80x9d means a C1-6 alkoxy group in which any of carbon atoms may be substituted with the halogen atom defined above, and examples of such groups include a trifluoromethoxy group, 2-chloroethoxy group, 1,2-dichloroethoxy group, 2-bromoethoxy group, 3-bromopropyloxy group, 3,3,3-trifluoropropyloxy group, 4-chlorobutyloxy group, 1,1-dimethyl-3-chloroethoxy group and 2,2-dimethyl-4-bromobutyloxy group.
In the specification, the xe2x80x9cC1-6 alkoxy group which may be substituted with a halogen atomxe2x80x9d has the same meanings as defined above.
In the phrase xe2x80x9cmay be substituted with a C1-6 alkyl group or acyl groupxe2x80x9d, the acyl group includes e.g. a formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, acryloyl group, methacryloyl group, crotonyl group, chloroformyl group, pivaloyl group, oxazalo group, methoxalyl group, ethoxalyl group and benzoyl group.
Hereinafter, the acyl group in the specification has the same meanings as defined above.
In the phrase xe2x80x9camino group which may be substituted with a C1-6 alkyl group or acyl groupxe2x80x9d, the amino group means an amino group which may be substituted with the same C1-6 alkyl group or the same acyl group as defined above, and examples of such groups include a N-formyl amino group, N-acetyl amino group, N-propionyl amino group, N-pivaloyl amino group, N-benzoyl amino group, N-methyl-N-formyl amino group, N-methyl-N-benzoyl amino group, N-methyl amino group, N,N-dimethyl amino group, N-methyl-N-ethyl amino group, N-(n-propyl) amino group, N-(i-propyl) amino group and N-(t-butyl) amino group.
Hereinafter, the xe2x80x9camino group which may be substituted with a C1-6 alkyl group or acyl groupxe2x80x9d in the specification has the same meanings as defined above.
In the formula (I), the xe2x80x9cC1-6 alkyl group which may be substituted with a halogen atomxe2x80x9d, the xe2x80x9cC3-7 cycloalkyl groupxe2x80x9d and the xe2x80x9cacyl groupxe2x80x9d in the definition of R2 and R3 have the same meanings as defined above.
Specifically, the xe2x80x9cC2-6 alkenyl groupxe2x80x9d means e.g. a vinyl group, allyl group, isopropenyl group, 1-propene-2-yl group, 1-butene-1-yl group, 1-butene-2-yl group, 1-butene-3-yl group, 2-butene-1-yl group and 2-butene-2-yl group.
In the formula (I), the xe2x80x9chalogen atomxe2x80x9d, the xe2x80x9cstraight or branched C1-6 alkyl group which may be substituted with a halogen atomxe2x80x9d, the xe2x80x9cC3-7 cycloalkyl groupxe2x80x9d, the xe2x80x9caryl group which may have a substituent groupxe2x80x9d, the xe2x80x9cC1-6 alkoxy group which may be substituted with a halogen atomxe2x80x9d and the xe2x80x9camino group which may be substituted with a C1-6 alkyl group or acyl groupxe2x80x9d have the same meanings as defined above.
The phrase xe2x80x9cC3-7 cycloalkoxy groupxe2x80x9d means cycloalkoxy groups that correspond to the C3-7 cycloalkyl groups defined above, and examples include a cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group and cyclohexyloxy group.
The phrase xe2x80x9caryl alkoxy groupxe2x80x9d means an alkoxy group having the same meanings as defined above except that it is substituted with an aryl group having the same meanings as defined above.
The phrase xe2x80x9cC1-6 alkylthio groupxe2x80x9d means alkylthio groups that correspond to the C1-6 alkyl groups defined above, and examples include a methyl thio group, ethyl thio group, n-propyl thio group, i-propyl thio group, sec-propyl thio group, n-butyl thio group, i-butyl thio group, sec-butyl thio group, t-butyl thio group, 1,2-dimethyl propyl thio group, 2-ethyl propyl thio group, 1,1-dimethyl butyl thio group, 2,2-dimethyl butyl thio group, 2- thyl butyl thio group and 1,3-dimethyl butyl thio group.
The phrase xe2x80x9cC1-6 alkoxy carbonyl groupxe2x80x9d means alkoxy carbonyl groups that correspond to the C1-6 alkoxy groups defined above, and examples include a methoxy carbonyl group, ethoxy carbonyl group, n-propoxy carbonyl group, i-propoxy carbonyl group, sec-propoxy carbonyl group, n-buthoxy carbonyl group, i-buthoxy carbonyl group, 1,2-dimethyl propoxy carbonyl group and 2-ethyl propoxy carbonyl group.
The phrase xe2x80x9cneighboring R3, R4, R5 and R6 may be combined to form a ring which may be substituted with a C1-6 alkyl groupxe2x80x9d means that neighboring groups among the substituent groups R3, R4, R5 and R6 may linked to one another to form a heterocyclic ring containing one or more atoms selected from the group consisting of a nitrogen atom, oxygen atom and sulfur atom, and this ring, together with carbon atoms in the benzene ring, forms a 5- to 7-memberred ring. Specifically, such a ring includes rings represented by the formula xe2x80x94Oxe2x80x94(CH2)nxe2x80x94oxe2x80x94 (n is an integer of 1 to 3), such as a 2,4-methylene dioxy ring as 5-memberred ring, 2,5-ethylene dioxy ring as 6-memberred ring and 2,6-propylene dioxy ring as 7-memberred ring.
Further, these alkylene dioxy rings may be substituted with C1-3 alkyl group. The C1-3 alkyl group corresponds to the C1-3 alkyl group out of the C1-6 alkyl group defined above, and examples include a methyl group, ethyl group, n-propyl group, i-propyl group and sec-propyl group.
In the phrase xe2x80x9cC1-6 alkylene group which may have a substituent groupxe2x80x9d in the definition of L in the formula (I), the alkylene group refers to a divalent group derived from a straight-chain C1-6 saturated hydrocarbon by removing one hydrogen atom from each of both terminal carbon atoms thereof. Specific examples include a methylene group, ethylene group, propylene group, butylene group, pentylene group and hexylene group, preferably methylene group, ethylene group, propylene group, butylene group and pentylene group, more preferably methylene group, ethylene group, propylene group and butylene group, further preferably methylene group and ethylene group.
In the phrase xe2x80x9cC2-6 alkenylene group which may have a substituent groupxe2x80x9d, the alkenylene group means a divalent group, which similar to the above-described alkylene group, is derived from a straight-chain C2-6 unsaturated hydrocarbon having a carbon-carbon double bond by removing one hydrogen atom from each of both terminal carbon atoms thereof. Specific examples include a vinylene group, propenylene group, butenylene group, pentenylene group and hexenylene group, preferably vinylene group, propenylene group, butenylene group and pentenylene group, more preferably vinylene group, propenylene group and butenylene group, further preferably vinylene group and propenylene group.
In the phase xe2x80x9cC2-6 alkynylene group which may have a substituent groupxe2x80x9d, the alkynylene group refers to a divalent group, which similar to the groups described above, is derived from a straight C2-6 unsaturated hydrocarbon having a carbon-carbon triple bond by removing one hydrogen atom from each of both terminal carbon atoms thereof. Specific examples include an ethynylene group, propynylene group, butynylene group, pentynylene group and hexynylene, preferably ethynylene group, propynylene group, butynylene group and pentynylene group, more preferably ethynylene group, propynylene group and butynylene group, further preferably ethynylene group and propynylene group.
In the formula xe2x80x94Exe2x80x94Gxe2x80x94, E is defined to be an oxygen atom, a sulfur atom, the formula xe2x80x94COxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N (R8)xe2x80x94 (wherein, R8 represents hydrogen atom, C1-6 alkyl group or acyl group), xe2x80x94N(R9)xe2x80x94COxe2x80x94 (wherein, R9 represents hydrogen atom or C1-6 alkyl group) or xe2x80x94(CH2)mxe2x80x94 which may have a substituent group (wherein, m is an integer of 0 to 6), and G is defined to be a sulfonyl group, the formula xe2x80x94N(R10)xe2x80x94 (wherein, R10 represents hydrogen atom, C1-6 alkyl group or acyl group) or xe2x80x94(CH2)nxe2x80x94 (wherein, n is an integer of 0 to 6).
Specifically, the following structures can be mentioned. 
When m is 0 in the above definition, E is a single bond so that the ring A is linked directly to G. When n is 0, G is a single bond so that the ring B is linked directly to E. When m and n are simultaneously 0, L as a whole represents a single bond so that the ring A is linked directly to the ring B. L may be bound to any position of the rings A and B.
X and Y are the same or different and represent a nitrogen atom, xe2x95x90CHxe2x80x94 or a carbon atom which may be substituted with a C1-6 alkyl group which may have a substituent group. The phrase xe2x80x9cmay be substituted with a C1-6 alkyl groupxe2x80x9d means that the carbon atom may be substituted with any of the C1-6 alkyl groups defined above.
However, the compounds represented by the formula (I) do not include those wherein X and Y are simultaneously carbon atoms which may be substituted with a C1-3 alkyl group, its salt or anhydrides thereof. The C1-3 alkyl group in this case means C1-3 alkyl groups out of the C1-6 alkyl groups defined above.
In the present invention, the salts include e.g. inorganic acid salts such as hydrofluorate, hydrochloride, hydrobromate, hydroiodate, sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate; organic carboxylic acid salts such as acetate, maleate, tartrate and fumarate; organic sulfonic acid salts such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate and toluene sulfonate; amino acid salts such as alginate, aspartate and glutamate; amine salts such as trimethyl amine salt, triethylamine salt, procaine salt, pyridine salt and phenethyl benzyl amine salt; alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as magnesium salt and calcium salt.
Although the dosage of the medicament according to the present invention is varied depending on the severeness of symptoms, age, sex, body weight, administration form and the type of disease, the medicament is given daily in one portion or in divided portions in a daily dose, per man, of usually about 30 xcexcg to 10 g, preferably 100 xcexcg to 5 xcexcg, more preferably 100 xcexcg to 100 mg for oral administration, or about 30 xcexcg to 1 g, preferably 100 xcexcg to 500 mg, more preferably 100 xcexcg to 30 mg for injection.
The administration form of the compound of the present invention is not particularly limited and may be administered orally or parenterally in a usual manner. For example, it can be administered as a pharmaceutical preparation in the form of e.g. tablets, powder, granules, capsules, syrups, troches, inhalations, suppositories, injections, ointments, eye ointments, eye drops, nose drops, ear drops, poultices and lotions.
These pharmaceutical preparations are produced in a usual manner by blending generally used ingredients as starting materials, where ordinarily used fillers, binders, lubricants, coloring agents, taste and odor correctives and as necessary stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives and antioxidants can be used for pharmaceutical manufacturing.
These ingredients include e.g. animal and vegetable oils such as soybean oil, tallow and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicon resin; silicon oil; surfactants such as polyoxyethylene fatty ester, sorbitan fatty ester, glycerin fatty ester, polyoxyethylene sorbitan fatty ester, polyoxyethylene hardened castor oil and polyoxyethylene polyoxypropylene block copolymer; water-soluble polymers such as hydroethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyvalent alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; and inorganic powder such as silicic anhydride, aluminum magnesium silicate and aluminum silicate, and pure water.
For example, the compounds represented by the formula (I) can be produced in the following manner. 
Wherein, X, Y, R1 to R7, ring A, ring B and L have the same meanings as defined above. Q means a halogen atom such as chlorine, bromine and iodine, or a hydroxyl group. In Production Method 1, Compound (i-1) having a nitro group is converted by reduction reaction into an amine (ii), and then (ii) is reacted with (iii) to give Compound (I-1) wherein L is e.g. xe2x80x94N(R9)xe2x80x94COxe2x80x94(CH2)nxe2x80x94 (R9and n have the same meanings as defined above), xe2x80x94N(R8) xe2x80x94SO2xe2x80x94 (R8 has the same meanings as defined above), xe2x80x94N(R8)xe2x80x94(CH2)nxe2x80x94 (R8 and n have the same meanings as defined above) etc.
The reduction reaction for obtaining (ii) from (i-1) can be conducted for example by catalytic hydrogenation with a catalyst, reduction with a metal such as iron and a metal salt, or by a metal-hydrogen complex compound having a Lewis acid or a metal salt combined with sodium borohydride, among which catalytic hydrogenation in a usual manner is most preferable when the compound has substituent groups which are stable even under catalytic hydrogenation. In the case of catalytic hydrogenation, any metal catalyst such as 10% palladium-carbon powder (hydrate), which allows the reaction to proceed, can be used. The solvent used may be any solvent which does not affect the reaction, and for example, an alcohol type solvent such as ethanol, an ether type solvent such as tetrahydrofuran or a mixed solvent thereof can be mentioned. By adding a tertiary amine such as triethylamine, further good results can also be obtained. If (i-1) has substituent groups which are not suitable for catalytic hydrogenation, the reduction thereof with a metal such as iron is preferable.
Preferable examples of (iii) are carboxylic acid compounds and sulfonic acid compounds having an eliminating group Q and a ring corresponding to the ring B. For example, a carbonyl chloride compound or a carboxylic acid compound corresponding to the ring B is allowed to react at room temperature to 60xc2x0 C. for 0.5 to 6 hours in the presence of an organic base such as pyridine and any salt such as potassium carbonate, sodium carbonate and barium carbonate, whereby Compound (I-1) wherein L is xe2x80x94N(R9)xe2x80x94COxe2x80x94(CH2)nxe2x80x94 (R9 and n have the same meanings as defined above) can be obtained. In other cases where (iii) is an alkyl halide compound, a sulfonyl chloride compound, an isocyanate compound, a 2,5-dimethoxy tetrahydrofuran compound or a phthalic carbaldehyde compound, each of these compounds is reacted with (ii), whereby Compound (I-1) can be obtained as its corresponding alkyl amino compound, sulfonamide compound, ureido compound, pyrolyl compound or isoindolynyl compound. The reaction solvent includes e.g. ether type solvents such as tetrahydrofuran and 1,4-dioxane, dimethylformamide, N-methyl-2-pyrrolidine, and a mixed solvent thereof, and the reaction can be conducted in the absence of a solvent. (I-1) can also be produced by reacting (ii) with the carboxylic acid compound in the presence of a dehydrogenation condensation agent and as necessary a tertiary amine such as triethylamine. In this case, further good results can be obtained by adding e.g. 1-hydroxybenzotriazole. The dehydration condensation agent includes e.g. N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide hydrochloride and dicyclohexyl carbodiimide, and the solvent includes e.g. acetonitrile, dimethylformamide and N-methyl-2-pyrrolidinone. 
Compound (I), wherein L is a single bond, a C2-6 alkenylene group which may have a substituent group or a C2-6 alkynylene group which may have a substituent group, can be produced by Production Method 2 shown above. In this reaction scheme, Compound (iv) means boric acid, dialkoxy borane, dialkyl borane and a trialkyl tin compound, all of which have a ring corresponding to the ring B, or the corresponding alkene or the corresponding alkyne.
In this method, (i-2) is reacted with (iv) in the presence of a catalyst. The reaction is conducted at about 40 to 80xc2x0 C. for approx. 1 to 24 hours in a nitrogen stream, where any solvent which does not affect the reaction, for example a 2-phase solvent composed of an organic solvent such as toluene, tetrahydrofuran and a mixed solvent thereof and 2 M aqueous sodium carbonate, and a mixed solvent of dimethylformamide and triethylamine, can be used. As the catalyst, any palladium complex allowing the reaction to proceed can be used, and tetrakis(triphenyl phosphine) palladium or bis(triphenyl phosphine) palladium chloride is preferably used. By adding copper iodide etc. depending on the case, further good results can be obtained.
Compound (I-2) obtained in this production method can be easily converted into Compound (I) wherein L is an alkylene chain. That is, Compound (I-2) wherein L is an alkynylene chain is subjected to an ordinarily known reaction of reducing xe2x80x94Cxe2x89xa1Cxe2x80x94, for example a reaction with a Lindlar catalyst/triethylamine etc., whereby Compound (I) having the desired alkylene chain can be easily obtained.
Compounds (i-1) and (i-2) in Production Methods 1 and 2 can be produced respectively in synthetic methods known in the art. One of such methods is Production Method 3 below. 
Production Method 3 is a method wherein (v) is reacted in the presence of a catalyst with (vi), that is, boric acid, dialkoxy borane, dialkyl borane or trialkyl tin compound, thus producing (vii), and (vii) is then reacted with an amine to produce the desired product (i) In the reaction scheme, R11 means a substituent group such as nitro group and halogen atom.
As the catalyst in the reaction of (v) with (vi), a non-valent or divalent palladium complex such as tetrakis(triphenyl phosphine) palladium can be used. The reaction can be conducted in a two-phase solvent of an organic solvent and 2 M aqueous sodium carbonate in a nitrogen stream at about 40 to 80xc2x0 C. for about 1 to 24 hours. Any solvent which does not affect the reaction can be used as the organic solvent, and for example, toluene, tetrahydrofuran and mixed solvents thereof can be mentioned. The reaction between (vii) and the amine can be conducted in a usual manner with or without the solvent at about 60 to 180xc2x0 C. for approx. 1 to 24 hours. In this case, any solvent which does not affect the reaction can be used, and preferable examples include alcohol type solvents such as isopropyl alcohol, ether type solvents such as tetrahydrofuran and 1,4-dioxane, dimethylformamide, N-methyl-2-pyrrolidinone, and mixed solvents thereof. In this reaction, further good results can be obtained by adding salts such as potassium carbonate, sodium carbonate and barium carbonate, and tertiary amines such as triethylamine, diisopropyl ethylamine and DBU, among which tertiary amines such as triethylamine, diisopropyl ethylamine and DBU are preferably used.
In the case of (v) wherein both X and Y are nitrogen atoms, the quinazoline compound (x) corresponding to (v) can be produced by Production Method 4 below. 
In this production method, a reaction product (ix) obtained from (viii) and urea is treated with a chlorinating reagent thereby producing (v). Herein, R12 may be a group such as C1-6 alkyl group insofar as xe2x80x94OR12 can function as an eliminating group. The reaction of (viii) with urea can be conducted with or without a solvent such as N-methyl-2-pyrrolidinone. In the reaction of obtaining (v) from (ix), e.g. a chlorinating reagent such as phosphorus oxychloride and phosphorus pentachloride can be used, and this reaction can be conducted in a solvent such as tertiary amine e.g. diisopropyl ethylamine or N,N-dimethylformamide, which does not adversely affect the reaction.
In the case of (vii) wherein both X and Y are nitrogen atoms, its corresponding quinazoline compound can be produced in Production Method 5 below. 
R11 in (xi) have the same meanings as defined above. The coupling of (x) with (xi) is conducted in the presence of an acid such as Lewis acid in any solvent not affecting the reaction. (xi) represents an aryl carbonyl halide which may have a substituent group, or its carboxylic acid, or heteroaryl carbonyl halide which may have a substituent group, or its carboxylic acids. As the Lewis acid, e.g. tin tetrachloride can be used. The solvent may be e.g. a halogen type solvent such as dichloromethane.
(xiii) is obtained by nitrating (xii) with a nitrating agent such as nitric acid, a mixed acid consisting of nitric acid and sulfuric acid, metal nitrates such as sodium nitrate and copper nitrate, acetyl nitrate, or nitronium salts such as nitronium tetrafluoroborate. As the nitrating agent, copper nitrate is particularly preferable. The solvent used may be any solvent such as acetic anhydride, which allows the reaction to proceed.
The reduction reaction of converting (xiii) into (xiv) can be conducted in the same manner as in the reduction reaction of (i-1) in Production Method 1. The reaction of (xiv) with urea can be carried out in a solution or suspension with or without the solvent at about 150 to 200xc2x0 C. for approx. 1 to 6 hours. The solvent is preferably e.g. N-methyl-2-pyrrolidinone etc.
The reaction of obtaining (xvi) from (xv) can be conducted in a usual manner by treating (xv) with phosphorus oxychloride or phosphorus pentachloride. Although any solvent which does not affect the reaction can be used, tertiary amines such as diisopropyl ethylamine, or N,N-dimethylformamide, is preferably used.
The above-mentioned compound (xiv) can also be produced in Production Method 6 below. 
Compound (xvii) can be obtained by treating (xvi) in the same manner as in the reduction reaction of (i-i) in the above Production Method 1. Compound (xviii) can be obtained by treating the resulting (xvii) with the corresponding carbonyl chloride compound or carboxylic acid compound in the same manner as in the acylation reaction for obtaining (I) from (ii) in the above Production Method 1.
The reaction of obtaining (xiv) from (xviii) can be conducted by the transition reaction of (xviii). That is, (xviii) is allowed to react together with a Lewis acid such as aluminum chloride with or without a solvent at about 180 to 250xc2x0 C. for approx. 0.1 to 2 hours, where any solvent not affecting the reaction can be used.
A typical process for producing Compound (I) wherein L is xe2x80x94COxe2x80x94N(R10)xe2x80x94 (R10 has the same meanings as defined above) is shown in Production Method 7 below. 
In this process, the desired compound (xxii) is produced by amidation of the xe2x80x94CHO group in (xx). First, the reaction of oxidizing the xe2x80x94CHO group in (xx) into xe2x80x94COOH group can be conducted in a usual manner by use of an usual oxidizing agent. For example, there is a method of reacting (xx) with a Jones reagent at about 0 to 80xc2x0 C. for approx. 1 to 6 hours in a solvent such as acetone not influencing the reaction. The amidation of the xe2x80x94COOH group in (xxi) can be effected in a usual manner by use of an amine compound corresponding to the ring B and a dehydration condensation agent. For example, Compound (xxi), the amino compound, the dehydration condensation agent and as necessary a tertiary amine such as triethylamine are dissolved in a solvent and reacted at about 0 to 60xc2x0 C. for approx. 1 to 24 hours, whereby the desired compound can be produced. In this case, further good results can be obtained by adding 1-hydroxybenzotriazole etc. Although the dehydration condensation agent may be any one which allows the reaction to proceed, N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexyl carbodiimide etc. are preferable. Although the solvent may be any solvent which does not influence the reaction, acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone etc. are preferable. Further, similar results can also be obtained by chlorinating it with thionyl chloride and subsequent reaction with the corresponding amine compound.
After the reaction is completed, the product can be purified as desired by conventional treatment methods such as column chromatography on silica gel, adsorption resin etc. or recrystallization from a suitable solvent.
The pharmacological actions of the compound according to the present invention were confirmed by the following test methods.
Inhibitory Action on PDE4: PDE4D was cloned from human placental mRNA by PCR techniques, and cDNA after an alternative spliced site (Mol. Cell. Biol., 13, 6558, 1993) was expressed in BHK cells. Two clones of BHK cells expressing PDE4 activity which was 100 or more times as high as endogenous PDE4 activity were obtained, and one of the clones was cultured in a large amount, and its homogenate was used as an enzyme source of PDE4.
50 mM Tris-HCl (pH 8.0), 0.1 mM EGTA, 0.1 mM MgCl2, 1 xcexcM [3H]-cGMP (100,000 dpm/tube) or 1 xcexcM [3H]-cAMP (100,000 dpm/tube) was added to the above homogenate, and 0.2 ml of the mixture was incubated at 30xc2x0 C. for 10 to 20 minutes in the presence or absence of a test compound. The enzyme reaction was stopped by incubating the mixture at 95xc2x0 C. for 1.5 minutes, and after cooling on ice, 50 xcexcl nucleotidase (10 units/ml) was added thereto and incubated at 30xc2x0 C. for 10 minutes. 550 xcexcl of AG1-X2 resin slurry (H2O:resin=2:1) was added to the reaction mixture, then left at 4xc2x0 C. for 10 minutes and centrifuged (10,000 rpm, 2.5 minutes, 4xc2x0 C.), and 450 xcexcl of the supernatant was measured for radioactivity.
The activity was compared in terms of IC50 (concentration of the compound at which 50% of the enzyme activity is inhibited) IC50 was determined by plotting of the concentration of cAMP as the substrate and the concentration of the compound on logarithmic graph paper. The results shown in Table 1 are the average in triplicate measurements. The test compound was first dissolved in DMSO and then diluted with the above-mentioned buffer for use.
Inhibitory Action on Production of TNF: Human peripheral blood was collected in (1%) and centrifuged (1000 rpm, 10 minutes, at room temperature) to remove platelet rich plasma, and then the blood sample was mixed with Hank""s balanced salt solution (HBSS) (with an equal volume to the removed plasma) containing penicillin (100 units/ml) and streptomycin (100 xcexcg/ml) (referred to hereinafter as xe2x80x9cp, sxe2x80x9d). Ficoll-paque (Pharmacia) with an volume of 3/5 relative to the sample mixture was layered on the lower layer and centrifuged at 1500 rpm for 30 minutes at room temperature, and the monocyte nucleus fraction was collected. The resulting monocyte nucleus fraction was washed twice with p, s-containing HBSS and prepared as a cell float at a cell density of 2-4xc3x97106 cells/ml in p, s-containing RPMI1640 (containing 10% FCS). 400 xcexcl of the prepared cell float was added to a 48-wells culture plate, and 50 xcexcl LPS (100 ng/ml of saline) and 50 xcexcl of each of compound solutions prepared at various concentrations were added to each well, followed by incubation at 37xc2x0 C. in a 5% CO2 mixed air. After incubation for 18 to 24 hours, the incubated buffer was separated, and TNFxcex1 thus released from the cells was measured by an ELISA kit (Amasham).
The inhibitory action of the compound on production of TNFxcex1 was determined in terms of IC50 by plotting the concentrations of the compound and the amount of produced TNFxcex1 (%relative to the control) on semilogarithmic graph paper. The control (100%) for the amount of TNFxcex1 produced was obtained by subtracting the amount of TNFxcex1 produced in the (basal) group where neither LPS nor the compound was added, from the amount of TNFxcex1 produced in the (control) group where the compound was not added. The results are shown in Table 2.
After the compound was dissolved at a concentration of 10 nM in DMSO solution containing the compound at a concentration which was 1000 times as high as the final concentration, and then the solution was diluted with RPMI1640 containing 10% FCS and p,s, to prepare a solution containing the compound at a concentration which was 10 times as high as the final concentration. In place of the compound solution, RPMI1640 (1% DMSO, 10% FCS) containing p, s was added to the control group basal group. In place of the LPS solution, physiological saline was added to the basal group.
Blood Sugar-Depressing Action (ZDP rat): A test compound was suspended in 0.5% MC, and the suspension was orally administered to an animal once every day for 1 week. After the administration, the rat was allowed to fast for 4 hours, and blood was collected from the tail vein, added immediately to 0.6 M HClO4 (0.6 M HClO4=1:9), and centrifuged to give a supernatant which was then measured for glucose level by Glocose CII Test Wako Kit (Wako Pure Chemical Industries, Ltd., JP). In the table, values in the parentheses under the blood sugar level (mg/dl) indicate glucose levels relative to those (=100%) before the administration of the test compound.
From the above results, the compound of the present invention is useful as a PDE4 inhibitor, and on the basis of this inhibitory action, the compound is further useful as an inhibitor of production of TNFxcex1. The compound of the present invention is very useful as a prophylactic and therapeutic agent for diseases in which cyclic AMP or TNFxcex1 is involved, such as inflammatory diseases such as arthritis, chronic joint rheumatism and asthma, immune diseases such as autoimmune disease, allograft rejection and graft versus host disease, central diseases such as multiple sclerosis, and sepsis, psoriasis and osteoporosis.
Further, the present inventors found that the compound of the present invention useful as a PDE4 inhibitor lowers blood sugar levels significantly in animals with diabetes. The compound of the present invention is also very useful as a prophylactic and therapeutic agent against diabetes.
Hereinafter, the present invention is described in more detail with reference to Production Examples and Examples. However, it goes without saying that the present invention is not limit thereto.

3.16 g of 3,4-dichloro-6,7-dimethoxy quinazoline, 2.04 g of 3-nitrophenyl boric acid and 1.00 g tetrakis(triphenyl phosphine) palladium were suspended in a mixed solvent of 200 ml toluene and 100 ml of 2 M aqueous sodium carbonate and stirred at 60xc2x0 C. for 15 hours in a nitrogen stream. The organic layer was recovered, washed with water and then with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=2:1). The product was recrystallized from ethanol to give 3.50 g of the title compound as colorless crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 3.92 (3H, s), 4.09 (3H, s), 7.19 (1H, s), 7.38 (1H, s), 7.80(1H, dd, J=8.2,7.7 Hz), 8.16 (1H, ddd, J=7.7,1.6,1.2 Hz), 8.44(1H, ddd, J=8.2,2.1,1.2 Hz), 8.68 (1H, dd, J=2.1,1.6 Hz).
m.p.; 228-230xc2x0 C. MASS 346 (MH30 )

Starting from 3-biphenyl boric acid (1.45 g) obtained from 3-bromobiphenyl according to the method of J. Org. Chem., 56, 3763, 1991. and 3,4-dichloro-6,7-dimethoxyquinazoline (1.50 g), 1.84 g of the title compound was obtained as a colorless crystals in the same manner as in Production Example 1.
1H-NMR (400 MHz, CDCl3) xcex4; 3.91 (3H, s), 4.08 (3H, s), 7.36 (1H, s), 7.37 (1H, s), 7.39 (1H, m), 7.47 (2H, m), 7.64 (1H, t, J=8.0 Hz), 7.65 (2H, m), 7.73 (1H, dt, J=8.0,1.6 Hz), 7.80 (1H, dt, J=8.0,1.6 Hz) 8.00 (1H, t, J=1.6 Hz).

1H-NMR (400 MHz, CDCl3) xcex4; 3.92 (3H, s), 4.08 (3H, s), 7.24 (1H, s), 7.35 (1H, s), 7.45 (1H, dd, J=7.9,7.7 Hz), 7.70 (1H, ddd, J=7.7,1.4,1.0 Hz), 7.77 (1H, ddd, J=7.9,2.0,1.0 Hz), 7.94 (1H, dd, J=2.0,1.4 Hz).

2.50 g of 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline obtained in Production Example 1,4.89 g methylamine hydrochloride and 11.0 g triethylamine were suspended in 25 ml 1-methyl-2-pyrrolidinone and stirred at 130xc2x0 C. for 18 hours in a sealed tube. Ethyl acetate and tetrahydrofuran were added thereto, and the reaction solution was washed with water 5 times and then with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:2). The product was recrystallized from tetrahydrofuran-ethyl acetate to give 1.89 g of the title compound as yellow crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 3.14 (3H, d, J=5.0 Hz), 3.82 (3H, s), 4.05 (3H, s), 5.14 (1H, br s), 6.97 (1H, s), 7.10 (1H, s), 7.74 (1H, dd, J=8.2,8.0 Hz), 8.07 (1H, ddd, J=8.0,1.8,1.1 Hz), 8.39 (1H, ddd, J=8.2,2.1,1.1 Hz), 8.62 (1H, dd, J=2.1,1.8 Hz). m.p.; 218-220xc2x0 C. MASS 341 (MH+)

Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 1.18 g ethylamine hydrochloride, 183 mg of the title compound was obtained as yellow crystals in the same manner as in Production Example 4.
1H-NMR (400 MHz, CDCl3) xcex4; 1.31 (3H, t, J=7.2 Hz), 3.59 (2H, m), 3.82 (3H, s), 4.04 (3H, s), 5.11 (1H, br s), 6.96 (1H, s), 7.08 (1H, s), 7.74 (1H, dd, J=8.2,7.7 Hz), 8.06 (1H, ddd, J=7.7,1.6,1.1 Hz), 8.39 (1H, ddd, J=8.2,2.2,1.1 Hz), 8.62 (1H, dd, J=2.2,1.6 Hz). m.p.; 164-166xc2x0 C. MASS 355 (MH30 )

Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 414 mg cyclopropylamine hydrochloride, 134 mg of the title compound was obtained in the same manner as in Production Example 4.
1H-NMR (400 MHz, CDCl3) xcex4; 0.62 (2H, m) 0.89 (2H, m) 2.93 (1H, m), 3.83 (3 H, s), 4.05 (3H, s), 5.38 (1H,br s), 6.98 (1H, s), 7.15 (1H, s), 7.74 (1H, dd, J=8.2,7.7 Hz), 8.07 (1H, ddd, J=7.7,1.4,1.1 Hz), 8.39 (1H, ddd, J=8.2,2.2,1.1 Hz), 8.62 (1H, dd, J=2.2,1.4 Hz). m.p.; 140-142 C. MASS 367 (MH+)

1.83 g of 6,7-dimethoxy-2-methylamino-4-(3-nitrophenyl) quinazoline obtained in Production Example 4,200 mg of 10% palladium-carbon powder (hydrate) and 1.44 g triethylamine were suspended in a mixed solvent of 10 ml ethanol and 10 ml tetrahydrofuran. After the atmosphere was replaced with hydrogen, the mixture was stirred for 15 hours at ordinary pressure at room temperature. The reaction solution was filtered, then the filtrate was evaporated, and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:3). The product was recrystallized from hexane-ethyl acetate to give 1.22 g of the title compound as pale yellow crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 3.11 (3H, d, J=5.2 Hz), 3.78-3.84 (5H, m), 4.03 (3H, s), 5.14 (1H,br s), 6.82 (1H, dd, J=7.9,2.2 Hz), 6.98 (1H, dd, J=2.2,1.8 Hz), 7.03 (1H, dd, J=7.7,1.8 Hz), 7.07 (1H, s), 7.14 (1H, s), 7.30 (1H, dd, J=7.9,7.7 Hz). m.p.; 197-199xc2x0 C. MASS 311 (MH+)

1.50 g of 4-(3-bromophenyl)-2-chloro-6,7-dimethoxyquinazoline obtained in Production Example 3 and 15 ml of 40% methylamine in methanol were suspended in a mixed solvent of 20 ml isopropanol and 20 ml tetrahydrofuran and stirred at 130xc2x0 C. for 9 hours in a sealed tube. Ethyl acetate was added thereto, and the reaction solution was washed with water twice and then with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (ethyl acetate). The product was recrystallized from hexane-chloroform to give 1.39 g of the title compound as pale yellow crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 3.11 (3H, d, J=5.1 Hz), 3.83(3H, s), 4.03 (3H, s), 5.15 (1H, m), 7.01 (1H, s), 7.07 (1H, s), 7.41 (1H, dd, J=7.9,7.7 Hz), 7.62 (1H, ddd, J=7.7,1.4,1.0 Hz), 7.65 (1H, ddd, J=7.9,2.0,1.0 Hz), 7.86 (1H, dd, J=2.0,1.4 Hz). m.p.; 246-248xc2x0 C. MASS 374, 376 (MH+)
1,2-Diethoxybenzene 
15.0 g of 2-ethoxyphenol, 18.0 ml of iodoethane and 30.0 g of potassium carbonate were suspended in 150 ml dimethylformamide, and the mixture was stirred at 80xc2x0 C. for 30 hours. Ethyl acetate was added thereto, and the mixture was washed with water for five times and with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound quantitatively as a red-brown oil.
1H-NMR (400 MHz, CDCl3) xcex4; 1.45 (6H, t, J=7.0 Hz), 4.09 (4H, q, J=7.0 Hz), 6.89 (4H, s).

18.9 g of 1,2-diethoxybenzene obtained in Production Example 9 and 22.0 g of 3-bromobenzoyl chloride were dissolved in 100 ml dichloromethane, and 100 ml of 1.0 M tin tetrachloride in dichloromethane was added dropwise thereto under ice-cooling. After the dropwise addition, the mixture was further stirred at room temperature for 15 hours. The reaction solution was poured into ice-cold water to terminate the reaction, and the organic layer was recovered, washed with water twice and with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was recrystallized from hexane-ethyl acetate to give 23.8 g of the title compound as colorless crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 1.46-1.52 (6H, m), 4.13-4.21 (4H, m), 6.89 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=8.8,2.0 Hz), 7.35 (1H, t, J=7.8 Hz), 7.46 (1H, d, J=2.0 Hz), 7.64-7.71 (2H, m), 7.88 (1H, t, J=l.6 Hz).

4-(3-Bromobenzoyl)-1,2-diethoxybenzene (20.7 g) obtained in Production Example 10 was dissolved in 80 ml of acetic anhydride, and then 4.5 ml of fuming nitric acid was added dropwise into the mixture under ice-cooling. After the dropwise addition, the mixture was further stirred 15 min under ice-cooling. The reaction mixture was poured into ice-cold water to cease the reaction, and then the resulting crystals were collected by filtration, washed with water and then air-dried to give 23.1 g of the title compound as yellow crystals.
1H-NMR (400 MHz , CDCl3) xcex4; 1.50 (3H, t, J=7.2 Hz), 1.55 (3H, t, J=7.2 Hz), 4.17 (2H, q, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 6.80 (1H, s), 7.31 (1H, t, J=8.0 Hz), 7.62 (1H, ddd, J=8.0,1.6,1.2 Hz), 7.68 (1H, ddd, J=8.0,1.6,1.2 Hz), 7.72 (1H, s), 7.87 (1H, t, J=1.6 Hz).

5-(3-Bromobenzoyl)-1,2-diethoxy-4-nitrobenzene (25.6 g) obtained in Production Example 11 and 16.5 g of iron (powder) were suspended in a mixed solvent of 300 ml of ethanol and 75 ml of acetic acid, and the mixture was heated under reflux for 2 hours. The solvent was evaporated, and then the resulting residue was suspended in ethyl acetate and filtered. The filtrate was evaporated, and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:1). The title compound was obtained quantitatively as yellow crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 1.33 (3H, t, J=7.2 Hz), 1.48 (3H, t, J=7.2 Hz), 3.85 (2H, q, J=7.2 Hz), 4.11 (2H, q, J=7.2 Hz), 6.17 (1H, s), 6.89 (1H, s), 7.32 (1H, t, J=8.0 Hz), 7.51 (1H, ddd, J=8.0,2.0,1.2 Hz), 7.61 (1H, ddd, J=8.0,1.2,0.8 Hz), 7.73 (1H, dd, J=2.0,0.8 Hz).

4-Amino-5-(3-bromobenzoyl)-1,2-diethoxybenzene (25.1 g) obtained in Production Example 12 and 50.0 g of urea were suspended in 15 ml of 1-methyl-2-pyrrolidinone, and the mixture was stirred at 200xc2x0 C. for 1 hour. Water was added thereto, and the resulting crystals were collected by filtration, washed with water and then air-dried to give 23.2 g of the title compound as yellow crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 1.29 (3H, t, J=7.2 Hz), 1.41 (3H, t, J=7.2 Hz), 3.91 (2H, q, J=7.2 Hz), 4.15 (2H, q, J=7.2 Hz), 5.47 (1H,br s), 6.17 (1H, s), 6.95 (1H, s), 7.54 (1H, t, J=8.0 Hz), 7.69 (1H, dd, J=8.0,1.6 Hz), 7.80 (1H, dd, J=8.0,1.6 Hz), 7.84 (1H, t, J=1.6 Hz).

4-(3-Bromophenyl)-6,7-diethoxy-2-quinazoline (11.5 g) obtained in Production Example 13 was suspended in 90 ml of phosphorous oxychloride, and the mixture was heated under reflux for 1 hour. The solvent was evaporated, and the resulting residue was suspended in dimethylformamide and then poured into ice-cold water. The resulting crystals were collected by filtration, washed with water and then air-dried to give 11.8 g of the title compound as yellow crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 1.50 (3H, t, J=7.2 Hz), 1.57 (3H, t, J=7.2 Hz), 4.09 (2H, q, J=7.2 Hz), 4.29 (2H, q, J=7.2 Hz), 7.21 (1H, s), 7.31 (1H, s), 7.44 (1H, t, J=8.0 Hz), 7.66-7.72 (2H, m) 7.92(1H, t, J=1.6 Hz).

Starting from 12.0 g of 4-(3-bromophenyl)-2-chloro-6,7-diethoxyquinazoline obtained in Production Example 14 and 60 ml of 40% methylamine in methanol, 10.7 g of the title compound was obtained as yellow crystals in the same manner as in Production Example 8.
m.p.; 130-132xc2x0 C. MASS 402, 404 (MH+)
1H-NMR (400 MHz, CDCl3) xcex4; 1.44 (3H, t, J=7.2 Hz), 1.54 (3H, t, J=7.2 Hz), 3.11 (3H, d, J=5.2 Hz), 4.00 (2H, q, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 5.12 (1H,br s), 7.02 (1H, s), 7.04 (1H, s), 7.40 (1H, t, J=8.0 Hz), 7.60 (1H, ddd, J=8.0,1.6,1.2), 7.64 (1H, ddd, J=8.0,1.6,1.2), 7.84 (1H, t, J=1.6 Hz).

Starting from 3.00 g of 3,4-dichloro-6,7-dimethoxyquinazoline and 2.47 g of 3-formylphenyl boric acid, 3.50 g of the title compound was obtained as colorless crystals in the same manner as in Production Example 1.
1H-NMR (400 MHz, CDCl3) xcex4; 3.90 (3H, s), 4.08 (3H, s), 7.23 (1H, s), 7.37 (1H, s), 7.78 (1H, t, J=7.6 Hz), 8.07 (1H, dt, J=7.6,1.4 Hz), 8.10 (1H, dt, J=7.6,1.4 Hz), 8.32 (1H, t, J=1.4 Hz), 10.15 (1H, s).

657 mg of 2-chloro-6i7-dimethoxy-4-(3-formylphenyl) quinazoline obtained in Production Example 16 was converted into a carboxylic acid compound by use of Jones reagent and then reacted with thionyl chloride in a usual manner to give 620 mg of the title compound as pale yellow crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 3.92 (3H, s), 4.09 (3R, s), 7 .21 (1H, s), 7.39 (1H, s), 7.77 (1H, t, J=8.0 Hz), 8.15 (1H, d, J=8.0 Hz), 8.32 (1H, d, J=8.0 Hz), 8.56 (1H, m).

Starting from 1.50 g of 2-chloro-6,7-dimethoxy-4-(3-formylphenyl)quinazoline and 15 ml of 40% methylamine in methanol, 1.00 g of the title compound was obtained as yellow crystals in the same manner as in Production Example 8.
1H-NMR (400 MHz, CDCl3) xcex4; 3.14 (3H, d, J=4.8 Hz), 3.80 (3H, s), 4.04 (3H, s), 5.13 (1H,br s), 6.99 (1H, s), 7.09 (1H, s), 7.72 (1H, t, J=7.6 Hz), 7.98 (1H, dt, J=7.6,1.4 Hz), 8.05 (1H, dt, J=7.6,1.4 Hz), 8.24 (1H, t, J=1.4 Hz), 10.13 (1H, s).

3.16 g of 6-benzyloxy-7-methoxy-2,4-quinazolindione obtained by esterifying 5-benzyloxy-4-methoxy-2-nitrobenzoic acid in a usual manner, then reducing its nitro group and cyclizing it with urea, and 10 ml N,N-diisopropyl ethylamine were suspended in 90 ml phosphorus oxychloride, and the mixture was heated under reflux for 1 hour. The solvent was evaporated, and then ethyl acetate was added to the resulting residue which was then washed with water 5 times and with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, whereby the title compound was obtained quantitatively as yellow crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 4.05 (3H, s), 5.31 (2H, s) 7.29 (1H, s), 7.34-7.45 (4H, m), 7.49-7.52 (2H, m).

3.66 g of 5-(3-bromobenzoyl)-1,2-dimethoxy-4-nitrobenzene, which was obtained from 1,2-dimethoxybenzene through the processes in Production Example 10 and then in Production Example 11 was subjected in a usual manner to Wittig-Horner reaction with diethyl cyanomethyl phosphonate, and the resulting crude product and 2.23 g iron were suspended in 40 ml methanol, and 20 ml conc. hydrochloric acid was added dropwise thereinto. After the dropwise addition, the mixture was heated under reflux for 8hours. The solvent was evaporated, then water was added to the residue, and the resulting crystals were collected by filtration. The crystals were returned to the free compound, and purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:3) to give 950 mg of the title compound as colorless crystals.
1H-NMR (400 MHz, CDCl3) xcex4; 3.80 (3H, s), 4.01 (3H, s), 4.59 (2H, m), 6.53 (1H, s), 6.93 (1H, s), 7.15 (1H, s), 7.36-7.44 (2H, m), 7.61 (1H, m), 7.65 (1H, dd, J=2.0,0.4 Hz).